Refractory Status Epilepticus Associated With a Pathogenic Variant in TNFRSF13B.

Febrile infection-related epilepsy syndrome (FIRES) is a rare epileptic syndrome characterized by new-onset refractory status epilepticus preceded by a febrile illness. Limited literature exists regarding the relationship between primary immunodeficiencies and immune-mediated epilepsy, and the relationship between new-onset refractory status epilepticus and common variable immunodeficiency (CVID) is not well-understood. We present a case of a 21-year-old female with a history of recurrent sinus infections, asthma, thrombocytopenia, atrioventricular nodal reentrant tachycardia, and neonatal seizures who presented with fever and new-onset status epilepticus. She was ultimately diagnosed with a heterozygous variant in TNFRSF13B c.311G>A (p.Cys104Tyr), which encodes for a tumor necrosis factor receptor implicated in CVID.

Survival Analysis of Immunotherapy Effects on Relapse Rate in Pediatric and Adult Autoimmune Encephalitis.

BACKGROUND AND OBJECTIVES: Prior observational studies for autoimmune encephalitis (AE) have mostly focused on outcomes after acute immunotherapies with better outcomes associated with earlier immunotherapy use. However, the impact of long-term immunotherapy and its association with clinical relapse is not well known. METHODS: We conducted a retrospective study of consecutive patients meeting published clinical criteria for AE evaluated at UC San Diego and Rady Children's Hospital from January 2007 to November 2021. Survival analysis and Cox multivariable regression models were used to evaluate relapse risk using rituximab exposure as a time-dependent variable. Pooled and age-stratified analyses were performed. RESULTS: A total of 204 pediatric and 380 adult participants were screened of which 30 pediatric and 75 adult participants were included. The most common antibody subtype in both cohorts was anti-NMDA receptor (76% in pediatric, 34% in adult). Relapses occurred in 31% of pediatric antibody-positive, 40% of adult antibody-positive, and 20% of adult antibody-negative cases. Times to first relapse (TTFR) were 10.6 ± 7.4 months (pediatric antibody-positive), 13.1 ± 24.5 months (adult antibody-positive), and 6.9 ± 3.8 months (adult antibody-negative). Rituximab was the most common second-line immunotherapy used. Combining pediatric and adult data, rituximab use was associated with a 71% lower hazard for time to first relapse (hazard ratio [HR] 0.29, 95% CI 0.09-0.85) and 51% lower hazard for recurring relapses (HR 0.49, 95% CI 0.9-1.26). The HR for TTFR with rituximab use in children was 0.30 (95% CI 0.05-1.69), 0.29 (95% CI 0.07-1.29) in adults, 0.32 in non-NMDA antibody-positive encephalitis (95% CI 0.07-1.39), and 0.42 (95% CI 0.07-2.67) for anti-NMDAR. DISCUSSION: Relapses are common in pediatric and adult patients with AE, although less frequently in anti-NMDARE. Using a rigorous survival model, we demonstrate a substantial benefit of rituximab use for reducing relapse rates in AE, especially for the adult population. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that rituximab is associated with a lower hazard to relapse in patients with AE.

Case report: Neuronal intranuclear inclusion disease presenting with acute encephalopathy.

Neuronal intranuclear inclusion disease (NIID), a neurodegenerative disease previously thought to be rare, is increasingly recognized despite heterogeneous clinical presentations. NIID is pathologically characterized by ubiquitin and p-62 positive intranuclear eosinophilic inclusions that affect multiple organ systems, including the brain, skin, and other tissues. Although the diagnosis of NIID is challenging due to phenotypic heterogeneity, a greater understanding of the clinical and imaging presentations can improve accurate and early diagnosis. Here, we present three cases of pathologically proven adult-onset NIID, all presenting with episodes of acute encephalopathy with protracted workups and lengthy time between symptom onset and diagnosis. Case 1 highlights challenges in the diagnosis of NIID when MRI does not reveal classic abnormalities and provides a striking example of hyperperfusion in the setting of acute encephalopathy, as well as unique pathology with neuronal central chromatolysis, which has not been previously described. Case 2 highlights the progression of MRI findings associated with multiple NIID-related encephalopathic episodes over an extended time period, as well as the utility of skin biopsy for antemortem diagnosis.

COVID-19-associated AMPA-R and CRMP-5 autoimmune encephalitis in a patient with thymoma and myasthenia gravis.

Thymomas are associated with autoimmune disease, most commonly myasthenia gravis, and rarely with autoimmune encephalitis. More recently, viral triggers including COVID-19 have also been implicated in autoimmunity. We present a case of antibody-positive autoimmune encephalitis that developed in the setting of COVID-19 in a patient with thymomatous myasthenia gravis.

Therapeutic Advances in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system that causes significant disability and healthcare burden. The treatment of MS has evolved over the past three decades with development of new, high efficacy disease modifying therapies targeting various mechanisms including immune modulation, immune cell suppression or depletion and enhanced immune cell sequestration. Emerging therapies include CNS-penetrant Bruton's tyrosine kinase inhibitors and autologous hematopoietic stem cell transplantation as well as therapies aimed at remyelination or neuroprotection. Therapy development for progressive MS has been more challenging with limited efficacy of current approved agents for inactive disease and older patients with MS. The aim of this review is to provide a broad overview of the current therapeutic landscape for MS.

Resolution of radiation necrosis with bevacizumab following radiation therapy for primary CNS lymphoma.

IMPORTANCE: Radiation necrosis (RN) is a rare but serious adverse effect following treatment with radiation therapy. No standard of care exists for the management of RN, and efforts to prevent and treat RN are limited by a lack of insight into the pathomechanics and molecular drivers of RN. This case series describes the outcomes of treatment with bevacizumab (BV) in two primary CNS lymphoma (PCNSL) patients who developed symptomatic biopsy-proven RN after whole brain radiation (WBRT) with a stereotactic radiosurgery (SRS) boost. OBSERVATIONS: Patient 1 is a 52 year-old female with PCNSL treated with WBRT followed by an SRS boost. She developed symptomatic biopsy-proven RN, and initial treatment with tocopherol and pentoxifylline was unsuccessful. A 100% clinical and radiographic response was achieved with 4 cycles of BV. Patient 2, a 48 year-old male with PCNSL, presented with seizures and biopsy-proven RN after radiation therapy. Initial empiric treatment with tocopherol and pentoxifylline was unsuccessful. A 100% clinical and radiographic response was achieved with 3 cycles of BV. CONCLUSIONS AND RELEVANCE: Monitoring for RN in patients with PCNSL treated with radiation therapy is warranted. BV is an efficacious treatment and a viable alternative to corticosteroids or surgical intervention.

Outcomes and Cost-Effectiveness of Autologous Hematopoietic Cell Transplant for Multiple Sclerosis.

PURPOSE OF REVIEW: This review presents a critical appraisal of the use of autologous hematopoietic cell transplant (AHCT) for the treatment of multiple sclerosis. We present the reader with a brief review on the AHCT procedure, its immunomodulatory mechanism of action in MS, the most recent evidence in support of its use in patients with relapsing-remitting multiple sclerosis (RRMS), as well as its cost considerations. RECENT FINDINGS: The first meta-analysis of clinical trials of AHCT for patients with MS demonstrated durable 5-year progression-free survival rates and low treatment-related mortality. Recently, the first randomized controlled phase III clinical trial demonstrated AHCT to be superior to best available therapy for a subset of patients with RRMS. This led to the American society for transplant and cellular therapies (ASTCT) to recommend AHCT "for patients with relapsing forms of MS who have prognostic factors that indicate a high risk of future disability." AHCT should be considered for patients with RRMS with evidence of clinical activity who have failed 2 lines of therapy or at least one highly active disease-modifying therapy.

Adjunctive perampanel for glioma-associated epilepsy.

Glioma-associated epilepsy is associated with excessive glutamate signaling. We hypothesized that perampanel, an amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, would treat glioma-related epilepsy. We conducted a single-arm study of adjunctive perampanel for patients with focal-onset glioma-associated seizures. The most common related adverse events were fatigue and dizziness. Three out of 8 participants had self-reported seizure reduction and an additional 3 reported improved control. Of these 6, 5 had isocitrate dehydrogenase 1 mutant gliomas. We conclude that perampanel is safe for patients with glioma-related focal-onset epilepsy. Further study into the association between AMPA signaling, IDH1 status and seizures is warranted.

Neurosarcoidosis following Immune Checkpoint Inhibition.

Recently, immune checkpoint inhibitors have revolutionized cancer care by enhancing anti-tumor immunity. However, by virtue of stimulating the immune system, they can lead to immune-related adverse events (irAEs). Neurologic irAEs are uncommon but are becoming increasingly recognized and can be quite serious or even fatal. Furthermore, central nervous system (CNS) manifestations may be difficult to distinguish from CNS metastases, posing management challenges. Here, we describe a patient who developed exacerbation of sarcoidosis leading to CNS involvement following dual checkpoint blockade with nivolumab and ipilimumab for metastatic melanoma and review the relevant literature.

Recurrent schilder's disease.

Schilder's disease is a rare and aggressive central nervous system demyelinating disorder that is typically monophasic and steroid responsive. Here, we present an unusual case of a teenager with Schilder's disease who was treated with corticosteroids and had a clinical and radiographic recurrence nearly one year after the initial presentation.

Nivolumab-Induced Autoimmune Encephalitis in Two Patients with Lung Adenocarcinoma.

Immune checkpoint inhibitors have improved patient survival outcomes in a variety of advanced malignancies. However, they can cause a number of immune-related adverse effects (irAEs) through lymphocyte dysregulation. Central nervous system (CNS) irAEs are rare, but as the number of indications for checkpoint inhibitors increases, there has been emergence of CNS immune-mediated disease among cancer patients. Given the relatively recent recognition of checkpoint inhibitor CNS irAEs, there is no standard treatment, and prognosis is variable. Therefore, there is a great need for further study of checkpoint inhibitor-induced CNS irAEs. Here, we present two unique cases of nivolumab-induced autoimmune encephalitis in patients with non-small cell lung cancer and review the available literature.

Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma.

Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, ex vivo analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8+ T-cell polyfunctionality in vivo when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8+ T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ+, TNFα+, and CCL3+ polyfunctional, CMV-specific CD8+ T cells. These increases in polyfunctional CMV-specific CD8+ T cells correlated (R = 0.7371, P = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study.Significance: A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. Cancer Res; 78(1); 256-64. ©2017 AACR.

Immunotherapy approaches in the treatment of malignant brain tumors.

Glioblastoma is the most common malignant primary brain tumor. Despite standard-of-care treatment, consisting of maximal surgical resection followed by chemoradiation, both morbidity and mortality associated with this disease remain very poor. Therefore, there is an urgent need for more efficacious and well tolerated therapies. Advancing knowledge of the intricate interplay between malignant gliomas and the immune system, coupled with the recent launch of immunotherapy research for other cancers, has led to a veritable increase in immunotherapy investigation for glioblastoma and other malignant gliomas. This clinical review highlights the recent breakthroughs in cancer immunotherapy and the complex correlation of the immune system with primary brain tumors, with special attention to multiple immunotherapy modalities currently being investigated for malignant glioma, including peptide vaccines, dendritic cell vaccines, oncolytic viruses, chimeric T-cell receptors, and checkpoint inhibitors. Cancer 2017;123:734-50. © 2016 American Cancer Society.

Single-Agent Carboplatin for a Rare Case of Pilomyxoid Astrocytoma of the Spinal Cord in an Adult with Neurofibromatosis Type 1.

INTRODUCTION: Pilomyxoid astrocytoma (PMA) is a rare and more aggressive variant of pilocytic astrocytoma, which usually affects young children and is most often located in the hypothalamic/chiasmatic region. The association of PMA with underlying genetic disorders is not well known. METHODS: We identified a 23-year-old woman with a PMA of the spinal cord who was simultaneously diagnosed with neurofibromatosis type 1. Diagnosis of neurofibromatosis type 1 was made clinically and confirmed with genetic testing that revealed a heterozygous one-amino-acid deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene, which is correlated with a milder phenotype. The patient underwent a partial surgical resection of the spinal cord tumor followed by adjuvant carboplatin 560 mg/m2 every 4 weeks. Radiation was avoided due to risks associated with neurofibromatosis type 1. RESULTS: At the 11-month follow-up, the patient maintained a partial radiographic response as well as complete resolution of her neurologic deficits. CONCLUSION: To our knowledge, this is the first reported case of an adult patient with neurofibromatosis type 1 and a spinal cord PMA. Single-agent carboplatin was effective and well-tolerated.

Postictal Magnetic Resonance Imaging Changes Masquerading as Brain Tumor Progression: A Case Series.

Seizures are common among patients with brain tumors. Transient, postictal magnetic resonance imaging abnormalities are a long recognized phenomenon. However, these radiographic changes are not as well studied in the brain tumor population. Moreover, reversible neuroimaging abnormalities following seizure activity may be misinterpreted for tumor progression and could consequently result in unnecessary tumor-directed treatment. Here, we describe two cases of patients with brain tumors who developed peri-ictal pseudoprogression and review the relevant literature.

Evidence of human immunodeficiency virus type 1 infection of nestin-positive neural progenitors in archival pediatric brain tissue.

Human immunodeficiency virus type 1 (HIV-1) central nervous system (CNS) infection in children is associated with impaired brain growth and neurodevelopmental delays. Neural progenitors are critical for neurogenesis. Human multipotential neural progenitors grown in culture are permissive for HIV-1 infection, but it is not known if infection of these cells occurs in vivo. Brain tissue from pre-highly active antiretroviral therapy (HAART) era pediatric acquired immunodeficiency syndrome (AIDS) patients was examined for evidence of HIV-1 infection of nestin-positive neural progenitors by in situ hybridization; or after laser microdissection harvest, DNA extraction, and polymerase chain reaction (PCR). HIV-1 or viral DNA was identified in nestin-positive cells in four of seven HIV-1-infected children, suggesting in vivo infection of neural progenitors.